Interorgan glutamine flow regulation in metabolic acidosis.
The flow of glutamine to the kidneys is essential for generating base in response to acid loading yet neither the magnitude nor direction of this flow are normally supportive of renal ammoniagenesis. However, chronic metabolic acidosis sets in motion regulatory systems enhancing flow magnitude as well as redirecting glutamine from the splanchnic bed and ureagenesis to the kidneys for ammoniagenesis and bicarbonate generation. These mechanisms include organ-specific inductions of glutamine synthesizing and hydrolyzing enzymes at the source, muscle, and the destination, kidneys, respectively; organ-specific shifts in fluxes through competing metabolic pathways favoring glutamine formation at the expense of the ureagenic precursor alanine and unique interorgan regulation whereby upstream sites modulate subsequent downstream sites by setting the glutamine loads and the release of glutamine metabolites acting as metabolic signals. These extrarenal regulatory mechanisms act in concert making glutamine available at the expense of ureagenesis. The kidneys draw upon plasma glutamine, despite a 40% reduction in the arterial concentration, generating base in the form of renal venous bicarbonate and excreting nitrogen and protons as ammonium. Underlying this enormous renal extraction is a shift in the uptake mode from a load- to a transport-limited process closely associated with the filtered bicarbonate load. Finally the interorgan glutamine flow set in motion during acidosis can be acutely reversed, revealing a hierarchal interaction of system subserving acid base and nitrogen balance. Thus, the extraordinary responses exhibited in chronic metabolic acidosis provide a superb model for discerning regulatory systems in other physiological as well as pathophysiological conditions.
Tamarappoo
B K
BK
Department of Physiology and Biophysics, Louisiana State University Medical Center, Shreveport.
Joshi
S
S
Welbourne
T C
TC
D000141:Acidosis, Renal Tubular / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D005973:Glutamine / Q000378:metabolism*; D009928:Organ Specificity
D005973:Glutamine